Primary lateral sclerosis (PLS) is a rare, sporadic upper motor neuron disorder thought to be a variant of the amyotrophic lateral sclerosis (ALS) family of motor neuron disorders. In PLS, motor neurons of the spinal cord and brainstem are clinically spared, in contrast to ALS patients. PLS patients typically have a normal lifespan, surviving more than a decade after symptoms begin. In this natural history study that began in FY2000, we previously showed that the rate of progression was most rapid in the first years after symptoms begin, often reaching a plateau after seven to eight years. This clinical course suggests that there may be a limited time window during which corticospinal neurons degenerate, and when potential interventions should be targeted. Unfortunately, making the diagnosis of PLS relies on clinical criteria that require symptoms to be present for 3-5 years without development of lower motor neuron signs. In the first several years of symptoms, clinical signs alone do not allow distinction between PLS and amyotrophic lateral sclerosis (ALS). A biomarker to help identify patients with PLS in the first years of symptoms is needed. The clinic was closed to new patients in 2016 with follow-up visits on enrolled patients held through spring 2019. In FY 19 we reported the results of a neuroimaging study to look for findings that emerge early, within the first years after the onset of symptoms. We collected clinical data and MRI scans on a cohort of patients with pre-PLS symptoms for 5 years or less, who were subsequently followed beyond 5 years of symptoms and met clinical criteria for the diagnosis PLS. We found reduced functional connectivity between the motor cortex and other regions of the brain in pre-PLS patients. This contrasts with reported findings in ALS patients. White matter changes also occurred in pre-PLS patients, but atrophy of the motor cortex was not seen. A larger prospective study comparing ALS and pre-PLS patients is needed to establish whether functional connectivity can be used to distinguish PLS from ALS in the first years of symptoms. In the second study in this project, whole genome sequencing in PLS and family members, analysis by collaborators continues with no clear associations to date.